Process for producing pregnanes

ABSTRACT

A PROCESS FOR PRODUCING 4,6-DIHALO-16-ALKYLIDENE PREGNA-4,6-DIENE-3,20-DIONES USEFUL AS PROGESTATIONAL AGENTS FROM A 16A,17A-EPOXY-3-ALKANOYLOXY-16-ALKYL-PREGN-5-EN20-ONE, AND INTERMEDIATES THEREOF.

United States Patent 3,657,227 PROCESS FOR PRODUCING PREGNANES RichardWightman Kierstead and Perry Rosen, North Caldwell, N.J., assignors toHolfmann-La Roche Inc., Nutley, NJ. No Drawing. Filed Dec. 11, 1969,Ser. No. 884,324 Int. Cl. C07c 173/00 US. Cl. 260-23955 21 ClaimsABSTRACT OF THE DISCLOSURE A process for producing4,6-dihalo-l6-alkylidene pregna-4,6-diene-3,20-diones useful asprogestational agents from al6a,l7a-epoxy-3-alkanoyloxy-16-alkyl-pregn-5-en- 20-one, andintermediates thereof.

SUMMARY OF THE INVENTION In accordance with this invention, a process isprovided for producing progestational agents of the formula:

a (I) wherein R and R, are chlorine or bromine; R is lower alkylidene;and R is hydrogen or lower alkanoyl,

from a compound of the formula:

wherein R is a lower alkanoyl; and R is lower alkyl,

via an intermediate of the formula:

(III) wherein R is as above; X is a halogen, and n is an in,-

teger from 0 to 5.

The compounds of Formula I above are highly valuable as progestationalagents have been prepared via dehydrogenation procedures that, in somecases, have proven expensive. By the series of selective reactions onthe steroid nucleus involved in the process of this invention, thecompound of Formula I above is produced in high yields without utilizingcostly dehydrogenation procedures and costly separation procedures thatcauses loss of yield.

DETAILED DESCRIPTION OF THE INVENTION As used herein, the term halogencomprehends all four halogens, such as chlorine, fluorine, bromine andiodine, with chlorine being the preferred halogen. The term lower alkyl,as used herein, comprehends both straight and branched chain saturatedhydrocarbon moieties having from one to six carbon atoms such as methyl,ethyl, t-butyl, n-pentyl or the like. The term halo lower alkyl includesmono and di-substituted halo lower alkyl moieties such as chloromethyl,2-chloroethyl, 3-bromopropyl, 1,2-dichloroethyl with chloromethyl beingpreferred. The preferred halo lower alkyl moieties are those halo loweralkyl moieties wherein the halo group is attached to the same carbonatom which is attached to the steroid nucleus. The term lower alkylideneindicates a straight or branched chain hydrocarbon moiety having fromone to six carbon atoms, the terminal carbon atom of which has two freevalence bonds such as methylene, ethylidene, isopropylidene and thelike, with methylene being preferred. The term lower alkanoylcomprehends residues of lower alkane carboxylic acids such as acetyl,butyryl, caprylyl or the like, containing from one to six carbon atoms.The term alkali metal" includes alkali metals such as sodium. potassiumand lithium.

The compounds of Formula I above are characterized by their high degreeof progestational activity. Thus, the compounds of Formula I above canbe administered enterally for example, orally or parenterally, withdosage adjusted to individual requirements, in the form of conventionalpharmaceutical preparations. For example, the compounds of Formula I canbe administered in conventional pharmaceutical solid or liquid forms,such as tablets, pills, capsules, solutions, suspensions, emulsions, orthe like. These pharmaceutical preparations can contain conventionalpharmaceutical carriers and excipients, such as water, talc, cornstarch, polyalkylene glycols, emulsifying agents, buffering agents,agents for the adjustment of osmotic pressure, Vaseline, and the like.Though it is preferred to administer the endocrinologically usefulcompounds of this invention enterally, the compounds of Formula I abovecan also be administered topically. For this purpose, i.e., topicaladministration, these compounds can be administered in conventionaltopical administration forms, such as ointments or creams, incombination with conventional topical carriers such as petrolatum,stearic acid or the like. Also compositions containing the activeingredient of this invention can be subjected to conventionalpharmaceutical processes such as sterilization or the like. Also, thepharmaceutical compositions of this invention can contain other activeingredients. Moreover, the endocrinologically active compounds can beadministered as feed additives, and for this purpose can be admixed withconventional animal feeds or conventional animal premixes. Though asindicated dosages of the endocrinologically useful compounds of thisinvention should be adjusted to individual needs, the compound ofFormula I above can be administered internally in daily dosage regimensof from about 0.005 mg./kg. to about 0.15 mg./kg. per day. The dosagescan be administered in unit or divided dosage forms.

The usefulness of the compounds of this invention as progestationalagents is indicated in animals, for example, the compound of thisinvention, when administered to estrogen primed immature female rabbitsfor five days shows the presence of progestational activity by asecretory type endometrial response observed on histological sectionsprepared from the rabbits uteri and examined mi:

croscopically. A maximal response is demonstrated by progesterone at 200mg./kg. for five days, where as a compound of Formula I such as4,6-dichloro-l7a-acetoxy-16- methylenepregna-4,6-diene-3,20-dione whichwhen administered to rabbits showed progestational activity at 10mcg./kg./day for so.

In accordance with the process of this invention, the compound ofFormula III above is prepared from the compound of Formula II above viathe following reaction scheme:

caxtcu l u wherein R R R R X, and n are as above.

The compound of Formula II is converted to the compound of Formula IV,via reaction step (a), by treating the compound of the Formula II with aperacid. Any conventional organic peracid can be utilized in effectingthis conversion. Among the organic peracids which can be utilized areincluded, peracetic acid, perbenzoic acid, m-chloroperbenzoic acid, etc.with m-chloroperbenzoic acid being the preferred acid. Generally, thisreaction is carried out in the presence of an inert organic solvent. Anyconventional inert organic solvent can be utilized in this reaction.Among the organic solvents which can be utilized in this reaction areincluded, the ether solvents such as diethyl ether, tetrahydrofuran, andthe chlorinated hydrocarbon solvents such as carbontetrachloride,chloroform, etc. The preferred organic solvents are the chlorinatedhydrocarbons. The reaction of step (a) can be carried out at anytemperature of from about C. to C. Generally, it is preferred to carryout this reaction at a temperature of from 5 C. to 5 C.

The compound of Formula IV above is converted to the compound of FormulaV by treating the compound of Formula IV with chromium trioxide. Thechromium trioxide oxidizing agent can be prepared as an aqueoussolution. Generally, this reaction can be carried out in the presence ofan inert organic solvent. Any conventional inert organic solvent such asthe ether solvents hereinfore mentioned, and the ketone solvents such asdiethyl ketone, dimethyl ketone, and methylethyl ketone can be utilizedin carrying out the reaction of step (b). The reaction of step (b) canbe carried out at any temperature of from -40" C. Generally, it ispreferred to carry out this reaction at a temperature of from about C.to about C.

The compound of FormulaV is Converted to the compound of Formula VI, viareaction step (c), by refluxing the compound of Formula V in thepresence of a strong acid. Any conventional strong acid can be utilizedin carrying out the reaction of step (c). Among the strong acids whichcan be utilized in accordance with this invention are included,p-toluene sulfonic acid, hydrohalic acids such as hydrogen bromide,hydrochloric. acid, etc. This reaction can take place by utilizing thestrong acid as the solvent medium. On the other hand, an inert organicsolvent such as benzene can be utilized in addition to the strong acid.Among the preferred organic solvents are included benzene, toluene, etc.In carrying out the reaction of step (0), room temperature andatmospheric pressure can be utilized. If desired, higher or lowertemperatures can also be utilized. Generally, it is preferred to carryout this reaction at the reflux temperature of the reaction medium wherep-toluene sulfonic acid and benzene are utilized.

The compound of Formula VI is converted to the compound of Formula VIIvia reaction step (d), by treating the compound of the Formula VI with ahalogen, preferably chlorine. This reaction is carried out in thepresence of a proton acceptor. Any conventional proton acceptors suchas, for example, nitrogen-containing heterocyclic bases, e.g., pyridine,picoline, or the like; or tri-lower alkyl amines, e.g., triethyl amine,etc. The preferred proton acceptor is pyridine. Generally, this reactionis carried out in an inert organic reaction medium. Any conventionalinert organic solvent can be utilized in carrying out this reaction.Generally, solvents such as hydrocarbon solvents, for example, benzene,toluene, etc.; ethers, for example, ethyl ether or dioxane; chlorinatedhydrocarbons, for example, chloroform, carbontetrachloride, ethylenechloride, or methylene chloride; or the like, are utilized. Generally,in carrying out this reaction it is preferred to utilize hydrocarbonssuch as benzene as the solvent medium. The halogen can be introducedinto the reaction medium by conventional techniques, e.g., a solutioncontaining the halogen can be introduced into the reaction medium. Thisreaction is preferably carried out at low temperatures, i.e., preferablybetween -40 C. and 35 C., more advantageously between 30 C. and 0 C.

The compound of Formula VII is converted, in reaction step (e), to thecompound of Formula VIII by treating the compound of Formula VII with adehydrating agent. Any conventional dehydrating agent can be utilized incarrying out this reaction. Among the preferred dehydrating agents areincluded, thionyl chloride, phosphoryl chloride, and methylchlorosulfite'." This reaction is carried out the presence of lafprotonacceptor. Any of the conchloridal such sis phosphorous pentabromide andphosphorous. pentachloride, If desired, nitrogen gas can be bubbled intothe reaction medium during the reaction to prevent loss of yield. Incarrying out this reaction, temperatures; of fromaboutl)? C. to 50 C.can be utilized. Generally, it is preferred to-carry out this reactionat, a temperature ofa frorn about C. to C.

It,has been found 1that if this reaction is carried out in .the presencegfan inorganic base the presence of the compoundof -the Formula IXTB inthe reaction. mixture is eliminated. Therefore, it is generallypreferredto carry out this. reaction inihe presenceof an inorganic baseso as to prevent theifor'mationof the compound IX-B :and loss of yieldof the compound oftFormula IX-A. Any

conventional inorganic base' can be utilized. Generally,

6 separating various by-products with a consequential loss of yield.

The compound of Formula IX-A can be converted to the compound of FormulaX, via reaction step (g) by ventional proton acceptorshereinbeforementioned can 5 treatment with a basic hydrolyzing agent. Any convenbeutilized. Among thejprefe'rr'ed proton acceptors are intional basichydrolyzing agent which includes the strong cluded pyridine andcollidine. The reaction of step (e) inorganic bases such as the alkalimetal hydroxide can is carried out at low temperatures. Generally,temperatures be utilized in carrying out this reaction. Any of theconoffrom about -50? C. to about 30 C. can be utilized. ditionsconventional in basic hydrolysis can be utilized In carrying out thisreaction, it is preferred to utilize a 1 in this conversion. temp r u ofma u The conversion of a compound of the Formula X to a I Acompound ofFormula VIIIfis converted to the comcompound of the Formula III, viareaction step (h), is pound of F rm la IXrAi a i p y treatcarried out bytreating the compound of the Formula X ing thefcompound of the FormulaVIII with a phosphowith an oxidizing agent. The oxidizing agentsutilized in rOus chloride or a" ph sp us 'l In s reaction, 1 thisreaction are: chromium trioxide in an organic solvent the compound ofthe Formula IX-B can be formed as such as glacial acetic acid oracetone; manganese dioxide; an impurity. This. impurity can be removedby conventhe Jones reagent (chromium trioxide in sulfuric acid andtional means such as colu'rn'n chromatography. This reacacetonesolvent); the Oppenauer reagent (aluminum tion is .carriedout in thepresence of an inert organic isopropoxide in ketone solvents such asacetone and solvent. Any conventional inert organic solvent can be 20cyclohexanone); or dichlorodicyanobenzoquinone. Any utilized in thisreaction, Among the conventional inert of the conditions conventional inutilizing these oxidizing organic solvents are included, hydrocarbonsolvents such agents can be utilized in carrying out the reaction of asbenzene and 'toluene;'halogenated hydrocarbon solstep (h). vents such asmethylene chloride,v chloroform, etc. The The intermediate III isconverted to the compound of halogenating agent can be any phosphorousbromide or 25 the Formula I by the following reaction scheme:

. M i 3 i i i i l c=o' .4

caxwag n caxtcng n R1 R2 x1 XIII wherein R R R X and n are as above.

The compound of Formula III is converted to the compound of Formula XI,via reaction step (i), by treating the compound of the Formula III witha halogen selected from the group consisting of chlorine or bromine.This step may be facilitated by the additionof a catalytic amount of ananhydrous mineral or organic acid. Among the preferred acids are thehydrohalic acids, e.g., hydrogen chloride, This reaction is generallycarried out in an inert organic reaction medium, for example, etherssuch as the lower 'alkyl ethers which include ethyl ether ordioxane;fhalogenated hydrocarbons such as chloroform,carbontet'rachloride, methylene chloride or ethylene chloride or thelike. The preferred' solvents for utilization in this reaction are thehalogenated hydrocarbons. The halogen can be introduced into thereaction medium by conventional means, e.g., a solution containing thehalogen can be introduced into the reaction mixture. A halogendissolvedin a halogenated hydrocarbon, for example, chlorine incarbontetrachloride is suitable for this purpose. This halogenationreaction is suitably efiected at low temperatures, preferably between 40C. and room temperature, or advantageously between-40 and 0 C.

The compound of Formula XI can be converted to the compound of FormulaXII, via reaction step (j), by treating the compound of Formula XI witha dehydrohalogenating agent. The dehydrohalogenating agents which areutilized in this reaction are preferably proton acceptors, such as forexample, nitrogen containing heterocyclic bases, e.g., pyridine,picoline or the like; or trilower alkyl amines, e.g., triethyl amine;and alkali metal inorganic bases such as sodium hydroxide or sodiumbicarbonate. A suitable solvent for use in this reaction is the baseitself. However, other solvents such as inert organic solvents, forexample, ethers such as lower alkyl ethers, which include diethyl etheror dioxane; chlorinated hydrocarbons such as chloroform orcarbontetrachloride may also be employed. This reaction is generallycarried out at temperatures of from about C. to 100 C., although atemperature range of 0-50 C. is preferred. The preferred base for use inthis reaction is a nitrogen containing heterocyclic base with pyridinebeing especially preferred.

The compound of Formula XII is converted to the compound of FormulaXIII, via reaction step (i) by refluxing the compound of Formula XIIwith an alkali metal iodide, preferably sodium iodide followed by theaddition of lower alkanoic acid. Alternatively, the compound of FormulaXII can be converted to the compound of Formula XIII by refluxing thecompound of Formula XII with an alkali metal iodide in the presence of alower alkanoic acid, preferably acetic acid. This reaction is generallycarried out in the presence of an inert organic solvent. Among thepreferred solvents are the ketone solvents such as acetone, methyl ethylketone, etc.

The compound of Formula XIII is converted to the compound of the FormulaI, by treating the compound of the Formula XIII with a lower alkanoicacid anhydride. Any of the conditions conventional in alkanoylatingreactions can be utilized in carrying out this reaction. Thealkanoylating reaction is carried out generally in the presence of anacid catalyst. Among the conventional acid catalysts which can beutilized in the reaction of step (h) are included the strong acids suchas p-toluene sulfonic acid, sulfuric acid, etc. In carrying out thisreaction, temperature and pressure are not critical and this reactioncan be carried out at room temperature. However, if desired, higher orlower temperatures can be utilized.

The following examples are illustrative of this invention but notlimitative thereof. All temperatures in the examples are stated indegrees centigrade.

EXAMPLE 1 Preparation of 55, 65, 160:, 17a-diepoxy-2B-hydroxy-16 8-methylpregnan-ZO-one acetate To a cooled solution (0) of 75 g. (0.194mole) of 16oz, 17a-epoxy-3fi-hydroxy-16B-methylpregn-5-en-20-one acetatein 750 ml. of chloroform was added 59.4 g. of m-chloroperbenzoic acid(85% activity). The mixture was stirred at 0- for 30 minutes after whichtime the precipitated mchlorobenzoic acid was filtered and washed with asmall amount of chloroform. The combined chloroform solution was washedwith 10% sodium thiosulfate, 0.1 N sodium hydroxide (until stronglybasic), and finally saturated sodium chloride solution. The chloroformsolution was dried (MgSO and the solvent was removed under reducedpressure. The residue was then triturated with diethyl ether to give55,65,16,l7m-diepoxy-3fi-hydroxy-16p-methylpregnan-20-one acetate.

EXAMPLE 2 Preparation of3;3,5a-dihydroxy-16/3-methyl-l6a,27aepoxypregnane-6,20-dione 3-acetateTo a suspension of 67 g. (0.17 mole) of5g,6.,16ot,17adiepoxy-3fl-hydroxy-l6 S-methylpregnan-20-one acetate in400 ml. of methyl ethyl ketone was added dropwise 75 ml. of an aqueouschromium trioxide solution. The temperature was maintained between 2025during the addition. After stirring for 30 minutes at this temperatureanother 35 ml. of the chromium trioxide solution was added dropwise andthe dark reaction mixture allowed to stir for another 45 minutes. Themixture was then added to 3 liters of ice water and the tan precipitatefiltered and washed thoroughly with water. The residue was driedovernight under house vacuum. Crystallization from methanol gave 35, 50cdihydroxy-16fl-methyl-16a,17a-epoxypregnane-6,20-dione 3-acetate.

EXAMPLE 3 Prepaartion of35,5a,17ot-trihydroxy-16-methylenepregnane-6,20-dione 3-acetate Amixture of 28 g. of 3fl,5a-dihydroxy-16,8-methyl-16a,-17a-epoxypregnane-6,20dione B-acetate, 0.48 g. of paratoluenesulfonicacid and 300 ml. of dry benzene was stirred and refluxed for 2 hours. Atthe end of this time the mixture was cooled (0) and the precipitate wasfiltered and washed with a small amount of ether to give33,5a,17a-trihydroxy-16-methylenepregnane-6,20-dione 3- acetate.

EXAMPLE 4 Preparation of 16fi-chloromethyl-3fi,5a-dihydroxy-16a,-

17a-epoxypregnane-6,20-dione 3-acetate To a stirred suspension of 27 g.(0.0647 mole) of 35,511, 17a-trihydroxy 16 methylenepregnane 6,20 dione3- acetate (M.P. 245250) in 540 m1. of dry benzene was added at 0", 5.75ml. of pyridine followed by the dropwise addition of 77.4 ml. of a 0.92molar solution of chlorine in carbon tetrachloride. At the end of theaddition, the reaction mixture was allowed to warm to 10 and stirred atthis temperature for 30 minutes. The white precipitate was filtered andwashed with benzene. The benzene solutions were combined and washed with5% sodium thiosulfate solution, 0.1 N hydrochloric acid solution,saturated sodium chloride solution, and then dried over magnesiumsulfate. The solvent was then removed under vacuum and the residuetriturated with diethyl ether to give 16/3-chloromethyl-3B,5a-dihydroxy16a,l7a-epoxypregnane-6,20-dione 3-acetate.

EXAMPLE 5 Preparation of16B-chloromethy1-3B-hydroxy-16a,17mepoxypregn-4-ene-6,20-dione acetateTo a stirred solution of 28.5 g. (0.063 mole) of 165-chloromethyl-3B,5a-dihydroxy 16a,17a-epoxypregnane- 6,20-dione 3-acetate(M.P. 205-210") in 285 ml. of dry pyridine at 0 was added dropwise 17.1ml. of thionyl chloride. After the addition was completed the reactionmixture was stirred for an additional 2 hours at 0. The reaction mixturewas then poured into 2 liters of ice Water and stirred for 15 minutes.The precipitates was filtered, washed with water and air dried for 2hours under house vacuum. The product was then dissolved in benzene; thesolution dried (MgSO heated with charcoal, filtered and the solventremoved under reduced pressure. Trituration of the residue with diethylether gave 16;8-chloromethyl-flfi-hydroxy :,17a epoxypregn 4 cue-6,20-dione acetate.

EXAMPLE 6 Preparation of 6-chloro-16/3-chloromethyl-3p-hydroxy-16a,17ot-epoxypregna-4,6-dien-20-one acetate To a stirred suspension of50 g. of sodium bicarbonate in 500 ml. of benzene was added 10 g. (0.023mole) of 16B-chloromethyl 3/3 hydroxy 16ot,l7oc epoxypregn-4-ene-6,20-dione acetate. With nitrogen bubbling through the mixture, 30g. of phosphorous pentachloride was added, and the mixture was stirredat room temperature for 30 minutes. The reaction mixture was then cooledto 0 and slowly added to two liters of an ice cooled aqueous solutioncontaining 3% by weight of sodium bicarbonate. After stirring for 30minutes the benzene layer was separated, washed with water, saturatedsodium chloride solution and then dried (MgSO The solvent was removedunder reduced pressure and the residue triturated with methanol to give6-chloro 16p chloromethyl-3B-hydroxy-16a,17ot-epoxypregna-4,6-dien-20-one acetate.

EXAMPLE 7 Preparation of 6-chloro-16(3-chloromethyl-3fi-hydroxy-16a,17a-epoxypregna-4,6-dien-20-one 'epoxypregna-4,6:dien-20-one asagwhite foam.

" (EXAMPLE 8 Preparation of 16,8-ch1oroniethyl-456-dichloro-16a,17u-

" epoxypregna-4,6-diene-3,20-dione To a solution -'of-3.5 g. of6+chloro-165-chloromethy1- 3fi-hydroxyel6a,l'la-epoxypregna 4,6dien-ZO-one in 35 ml. of.alcohol-free acetone wasadded dropwise at 3.5ml. of] ones reagent. After minutes one ml. of isopropyl alcohol wasadded and the solvent removed under reduced pressure. Water (100 ml.)was added to the residue and the mixture extracted with diethyl ether.The ether solution was washed with an aqueous solution containing 5% byWeight of sodium'bicarbonate, a saturated aqueous sodium chloridesolution and dried (MgSO The solvent was then removed under reducedpressure to give crude 16,8-chloromethyl 6 chloro 16a,17a epoxy-'pregna-4,6-diene-3,20-dione. The crude product was dissolved in aminimum" of benzene and passed through 30 g. of silica gelJThe columnwas eluted with 500 ml. of 2% ethylacetate-benzene to give16B-chloromethyl-6-chloro-16:1,17a-epoxypregna 4,6 diene-3,ZO-dione.

'To'a cooled (0) solution of 2.3 grof 16,8-chloromethyl- 6-chlo'ro16a,17a-epoxypregna-4,6-diene-3,20-dione in 20 inL'of chloroform wasadded 7.3 ml. of a 0.85 molar solution of chlorine'in carbontetrachloride. The reaction mixture was stirredat 0 for 45 minutes'andthe solvent was then removed under reduced pressure. The residue was'treatedwith mli'of pyridine and stirred at room temperature for 2'hours. The pale yellow mixture was poured into 150 ml. of diethyl etherand the ether solution extracted several times with dilute sulfuric acidto remove all of the pyridine. Th'e'ether solution was then washedwith"asat-iirated aqueous sodium chloride solution, dried -(-MgSO ),"andthe ether removed under reduced pressure.

The residue was triturated with diethyl ether to give 165- chloromethyl4,6 dichloro' 16a,17a-epoxypregna-4,6- diene-3, 20 -dione....

I 1 EXAMPLE, 9.

7 Preparation of '4,6 dichloro-l7whydroxy-l6-methyleneprieg uaflgodiene-li,ZQ-dione acetate Tot-a stirred suspension of 3 g. "sodiumiodide in 20 ml: of acetone was added *300 mg. of 16,8-chloromethyl- 4,6-"dichloro -;"-l611,1'Zu-epoxypregna-4,6-diene-3,20-dioneandthe'mixturewasrefluxed for 24.hours. At the end of this .time 0.5,ml. ofnglacial acetic acid was added and refiuxing..-was" continuedfor-'an additional 2 hours. To the cooled dark solution was added ml. of0.1 N

sodium thiosulfate solutionand the acetone was then removed underreduced pressure. Water was added to the residue and the piecipitate wasfiltered and washed thoroughly with water. The product was dried for 2hours under vacuum and was then dissolved in a minimum amount of ether.The yellow ether solution was washed 10 with 0.1 N sodium thiosulfatesolution, dried (MgSO and evaporated to give4,6-dichloro-l7a-hydroxy-16- methylenepregna-4,6-diene-3,20-dione whichwas used directly for the next step.

A mixture of 200 mg. of crude4,6-dichloro-l7a-hydroxy-l6-methylenepregna-4,6-diene-3,20-dione, 1 ml.of acetic anhydride and 25 mg. of p-toluene sulfonic acid mono-hydratewas allowed to stir at room temperature for 3 hours. Water (50 ml.) wasthen added and the mixture was stirred for 1 hour. The precipitate wasfiltered, washed with water, and dried for 2 hours under hose vacuum.The product was then dissolved in a minimum of methylene chloride anddried (MgSO The solvent was removed under reduced pressure and theresidue was crystallized from methanol to give4,6-dichloro-17a-acetoxy-16- methylenepregna-4,6-diene-3,20-dione.

We claim:

1. A pregnane of the formula:

wherein R is lower alkanoyl; R is lower alkyl and CHX(CH H; Y is anunsaturation between the 4 and 5-positions; X is a halogen; m is aninteger from 0 to 1; and n is an integer from O to 5, with the provisothat when m is 1, the pregnane is unsubstituted at the 5- position.

2. The pregnane of claim 1 wherein said pregnane is 3,8,5a dihydroxy16/3 methyl-16a,17a-epoxypregnane- 6,20-dione 3-acetate.

3. The pregnane of claim 1 wherein said pregnane is chloromethyl 3535adihydroxy 16a,17u-epoxypregnan-6,20-dione 3-acetate.

4. The pregnane of claim 1 wherein said pregnane is 165 chloromethyl 3Bhydroxy 16ot,17nt-epoxypregn- 4-ene6,20-dione acetate.

5. A pregnane of the formula:

wherein R is lower alkylidene and R is lower alkanoyl. 6. The pregnaneof claim 5 wherein said pregnane is 3B,5ot,17atrihydroxy-16-methylenepregnan-6,20-dione 3- acetate. i i

7. A pregnane of the formula:

wherein R is chlorine or bromine; X is a halogen; R is lower alkanoyl;and n is an integer from O to 5;

comprising treating a diketo compound of the formula:

wherein R X and n are as above;

with a phosphorous chloride or phosphorous bromide in an inert organicsolvent medium at a temperature of from 0 C. to 50 C.

11. The process of claim wherein said diketo compound is treated withphosphorous pentachloride.

12. The process of claim 11 wherein an inorganic base is present in thereaction medium.

13. The process of claim 12 wherein said inorganic base is selected fromthe group consisting of alkali metal carbonates and alkali metalbicarbonates.

14. The process of producing a compound of the formula:

wherein R is lower alkanoyl; X is a halogen; and n is an integer from 0to 5;

comprising treating a dihydroxy compound of the formula:

wherein R is as above; and R is lower alkylidene;

with a halogen in the presence of a proton acceptor.

15. The process of claim 14 wherein said proton acceptor is pyridine andsaid halogen is chlorine;

16. A process of producing a compound of the formula:

jonxwnnnn 0 wherein R is lower alkanoyl; X is a halogen; and n is aninteger from 0 to 5;

comprising treating a compound of the formula:

i l l I I l OH wherein R X and n are as above;

with a dehydrating agent in the presence of a proton acceptor.

17. The process of claim 16 wherein said dehydrating agent is thionylchloride.

18. The process of claim 17 wherein said proton acceptor is pyridine.

19. A process for producing a compound of the formula:

14 wherein R is loweralkanoyl; and R is lower alkyl; wherein R is loweralkanoyl; and R is lower alkyl; comprising treating the eompound of'formula: comprising treating a compound of the formula:

" on, CH3 5 y R50 0' wherein R and R are as above; Whe e R5 and e 'fias' with an organic per-acid at a temperature of from about I a 0 --10C. to 50 C. l gg gm w moxlde at a temperature of from 21. The proeess ofclaim 2 0 wherein said organic per- 201 A process for producing acompound of the foracld m'chloroperbenzolc acld' mula: CH 20 ReferencesCited :6 UlfIITED STATES PATENTS 1 3,527,778 9/1970 Baran et a1.260-39745 R. 'OTHER REFERENCES Steroid Reactions, by Djerassi (1963),Holden-Day Inc., pp. 101, 111 relied on.

ELBERT ROBERTS, Primary Examiner R50 i 3 us. c1. X.R. 5 260397.4 0H

